P1031: PRELIMINARY DATA FROM THE PHASE 1/2 STUDY OF TP-3654, AN INVESTIGATIONAL SELECTIVE PIM1 KINASE INHIBITOR, SHOWED CYTOKINE REDUCTION AND CLINICAL RESPONSES IN RELAPSED/REFRACTORY MYELOFIBROSIS
Authors: Firas El Chaer, Lindsay Rein, Kazuya Shimoda, Junichiro Yuda, Tamanna Haque, James Mccloskey, Akiyoshi Takami, Masafumi Fukaya, Shuichi Shirane, Sujan Kabir, Jian Mei, Zhonggai LI, Mark Wade, Claudia Lebedinsky, Raajit K Rampal
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: The constitutively active PIM1 serine/threonine kinase is highly expressed in hematologic malignancies including myelofibrosis (MF) and has been shown to play a role in modulating the activity of the cytokine-induced PI3K/AKT and JAK-STAT pathways. Upregulation of inflammatory cytokines are thought to play a key role in the pathobiology of MF. In preclinical studies, TP-3654, a highly selective PIM1 kinase inhibitor, showed spleen size reduction and bone marrow (BM) fibrosis reversion in JAK2V617F murine MF models (Dutta A, 2021). Importantly, TP-3654 also showed reduction of cytokine response genes and serum TGF-β in progenitor cells and JAK2V617F murine MF model, respectively. TP-3654 is currently being evaluated in patients with MF previously treated with JAK inhibitors (NCT04176198). Aims: This Phase 1/2 study aims to identify MTD and/or RP2D and to evaluate safety and efficacy of oral TP-3654 monotherapy in patients with MF. In addition, the study aims to evaluate pharmacodynamic markers changes (cytokine profile, bone marrow fibrosis etc.) in MF patients treated with TP-3654. Methods: Key eligibility criteria for this study include primary or secondary MF; DIPSS intermediate- 1, 2 or high-risk MF; previously treated with or ineligible for JAK inhibitors; platelet count ≥25x109/L; splenomegaly (≥450 cm3 by imaging); and ≥2 measurable symptoms. Spleen volume reduction (SVR) evaluated by imaging, ≥50% total symptom score (TSS) improvement assessed by MFSAF v4.0, and cytokines assessed by multiplexed immunoassay of plasma. Results: As of 09 Feb 2023, 15 patients were enrolled across 5 dose levels from 480 mg QD to 720 mg BID. At baseline, median age 69 years (range, 61 to 77), spleen volume 1936 cm3 (range, 857 to 4408), total symptom score 18.6 (range, 4 to 62), platelet count 129 x109/L (range, 64 to 520), hemoglobin 9.7 g/dL (range, 5.9 to 13.7), and 5 patients required RBC transfusion. All patients had received prior treatment with at least one JAK inhibitor. Median duration of prior JAK inhibitors treatment was 12.8 months (range, 2.3 to 72.9). No DLTs occurred. The most common treatment-related adverse events (TRAEs) in ≥20% of patients included mild to moderate nausea, vomiting, and diarrhea. No hematological TRAEs reported. SVR observed in 8 of 10 evaluable patients treated for ≥12 weeks (median best change -13%, range -3% to -42%, 2 patients showed ≥35% SVR). TSS improvements observed in 9 of 10 evaluable patients (median best change -70%, range -31% to -100%, 6 patients showed ≥50% TSS response). Broad reductions in cytokines (e.g., IL-6, IL-8, IL-10, EN-RAGE) were observed after TP-3654 treatment. Cytokine modulation was observed as early as within the first 24 hours. At week 12 analysis, patients with higher cytokine reductions correlated with higher TSS improvement (Figure 1). BM fibrosis reduction from grade 3 to 2 was seen in one patient who also achieved spleen and symptoms responses and showed reductions in MF associated cytokines: IL6 (68%), IL12p40 (83%), MMP9 (56%), and EN-RAGE (68%), and is on active treatment for more than 18 months. Enrollment is ongoing, additional data will be presented. Summary/Conclusion: Preliminary cytokine data showed that TP-3654 monotherapy may prompt early cytokine changes that may correlate with symptoms response. In addition, preliminary data of TP-3654 in relapsed/refractory MF patients showed SVR, TSS improvement, and BM fibrosis reduction. In the dose ranges evaluated to date, TP-3654 has been well tolerated with no myelosuppressive TRAEs.Keywords: Myeloproliferative disorder, Idiopathic myelofibrosis, Myelofibrosis